6-pyrimidin-isoindole derivative as ERK1/2 inhibitor

Abstract

This invention relates to the compound (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide, and in particular to novel physical forms of the compound, a process for preparing the compound and synthetic intermediates for use in the process, and novel formulations containing the compound, as well as therapeutic uses of the compound.

The invention claimed is: 
     
       1. A method for:
 (a) the treatment of a disease state or condition mediated by ERK1/2; or 
 (b) the treatment of cancer, wherein said cancer is selected from a haematological malignancy or condition of lymphoid lineage or of myeloid lineage, pancreatic cancer, thyroid cancer, leukemia, lymphoma, glioma, and glioblastoma; or 
 (c) the treatment of hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung, breast, bladder, gastrointestinal, ovarian or prostate cancer; or 
 (d) the treatment of a disease or condition being characterized by mutant Ras, mutant BRAF or mutant MEK, 
 
       said method comprising administering to a subject a therapeutically effective amount of a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       or a tautomeric form thereof, in a substantially crystalline form. 
     
     
       2. The method according to  claim 1 , for:
 a) the treatment of haematological malignancies; or 
 b) the treatment of leukemias and lymphomas; or 
 c) the treatment of haematological malignancies and related conditions of lymphoid lineage; or 
 d) the treatment of haematological malignancies and related conditions of myeloid lineage; or 
 e) the treatment of adenomas and carcinomas; or 
 f) the treatment of disease states or conditions selected from tumours of epithelial origin; haematological malignancies and premalignant haematological disorders and disorders of borderline malignancy; tumours of mesenchymal origin; neural crest cell-derived tumours; tumours of the central or peripheral nervous system; endocrine tumours; ocular and adnexal tumours; germ cell and trophoblastic tumours; and paediatric and embryonal tumours; or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy; or 
 g) the treatment of pancreatic cancers; or 
 h) the treatment of NRas melanoma and NRas AML; or 
 i) the treatment of KRas lung cancer, KRas pancreatic cancer or KRas colorectal cancer (CRC); or 
 j) the treatment of BRAF colorectal cancer (CRC), BRAF lung cancer or BRAF melanoma. 
 
     
     
       3. The method according to  claim 2 , for:
 the treatment of haematological malignancies and related conditions of lymphoid lineage, selected from acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas, follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukaemias, natural killer [NK] cell lymphomas, Hodgkin's lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders; or 
 the treatment of haematological malignancies and related conditions of myeloid lineage selected from acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia. 
 
     
     
       4. The method according to  claim 3 , wherein the B-cell lymphoma is diffuse large B-cell lymphoma [DLBCL], and wherein the myeloproliferative disorder is polycythaemia vera, essential thrombocythaemia or primary myelofibrosis. 
     
     
       5. The method according to  claim 1 , wherein the compound is used in combination with one or more other compounds or therapies. 
     
     
       6. The method according to  claim 1 , wherein the substantially crystalline form of the compound of formula (1) or a tautomeric form thereof is a hydrate. 
     
     
       7. The method according to  claim 6 , wherein the substantially crystalline form of the compound of formula (1) or a tautomeric form thereof is a monohydrate. 
     
     
       8. The method according to  claim 1 , wherein the compound of formula (1) is at least 55% crystalline. 
     
     
       9. The method according to  claim 1 , wherein the compound of formula (1) has an X-ray powder diffraction pattern characterized by the presence of major peaks at the diffraction angles 14.0° and/or 20.6° and/or 24.0° and/or 24.2° (±0.2°). 
     
     
       10. The method according to  claim 1 , wherein the compound of formula (1) has an X-ray powder diffraction pattern characterized by the presence of major peaks at the diffraction angles and interplanar spacing set forth in Table A: 
       
         
           
                 
                 
                 
               
                     
                   TABLE A 
                 
                     
                     
                 
                     
                   Diffraction Angle (°)  
                   Relative Intensity 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   14.0 
                   100 
                 
                     
                   20.6 
                   85 
                 
                     
                   24.0 
                   74 
                 
                     
                   24.2 
                   71. 
                 
                     
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
       11. The method according to  claim 10 , wherein the X-ray powder diffraction pattern of the compound of formula (1) is further characterized by the presence of one or more additional peaks at the diffraction angles and interplanar spacings set forth in Table B: 
       
         
           
                 
                 
                 
               
                     
                   TABLE B 
                 
                     
                     
                 
                     
                   Diffraction Angle (°)  
                   Relative Intensity 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   8.8 
                   23 
                 
                     
                   13.0 
                   23 
                 
                     
                   13.8 
                   39 
                 
                     
                   14.4 
                   20 
                 
                     
                   17.3 
                   22 
                 
                     
                   19.3 
                   36 
                 
                     
                   21.3 
                   45 
                 
                     
                   28.7 
                   22. 
                 
                     
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       12. The method according to  claim 1 , wherein the compound of formula (1) exhibits peaks at substantially the same diffraction angles as those of the X-ray powder diffraction pattern shown in  FIG.  2   . 
     
     
       13. The method according to  claim 1 , wherein the compound of formula (1) has an X-ray powder diffraction pattern substantially as shown in  FIG.  2   . 
     
     
       14. The method according to  claim 1 , wherein the compound of formula (1) exhibits an endothermic event having an onset temperature between 100° C. to 110° C. when subjected to differential scanning calorimetry. 
     
     
       15. The method according to  claim 14 , wherein the compound of formula (1) exhibits an endothermic event having an onset temperature between 101° C. to 108° C. when subjected to differential scanning calorimetry. 
     
     
       16. The method according to  claim 1 , wherein the compound of formula (1):
 exhibits an endothermic event having a peak between 110° C. and 125° C. when subjected to differential scanning calorimetry; and/or 
 exhibits a weight loss between 85° C. and 130° C. when subjected to thermogravimetric analysis. 
 
     
     
       17. The method according to  claim 16 , wherein the compound of formula (1):
 exhibits an endothermic event having a peak between 111° C. and 113° C. when subjected to differential scanning calorimetry; and/or 
 exhibits a weight loss at 90-120° C. when subjected to thermogravimetric analysis. 
 
     
     
       18. The method according to  claim 1 , for the treatment of a disease state or condition mediated by ERK1/2. 
     
     
       19. The method according to  claim 1 , for the treatment of hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung, breast, bladder, gastrointestinal, ovarian or prostate cancer. 
     
     
       20. The method according to  claim 1 , for the treatment of cancer, wherein said cancer is selected from a haematological malignancy or condition of lymphoid lineage or of myeloid lineage, pancreatic cancer, thyroid cancer, leukemia, lymphoma, glioma, and glioblastoma.